OP0016 ABATACEPT TO SILENCE ANTI-CITRULLINATED PROTEIN ANTIBODY-EXPRESSING B CELLS IN RHEUMATOID ARTHRITIS: THE ASCARA TRIAL
Authors: N. Blomberg, J. Kwekkeboom, S. Böhringer, T. Huizinga, R. Toes, H. U. Scherer
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rheumatoid arthritis (RA) is one of the most prevalent systemic autoimmune diseases. Despite clinically effective drugs, RA remains a chronic disease with frequent disease flares upon drug tapering. Patients harbouring anti-citrullinated protein antibodies (ACPA) most frequently relapse and rarely achieve drug-free remission. We observed that in established RA, ACPA-expressing memory B cells (mBC) are highly activated, proliferate, secrete pro-inflammatory cytokines and differentiate into plasmablasts [1]. This phenotype points to continuous, T helper cell-driven stimulation of the ACPA B cell response and persists in patients in clinical remission induced by conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), suggesting ongoing immunological disease activity (IDA) despite clinically quiescent disease. Persistent IDA may be responsible for disease flares, making immunological remission a potential treatment target required for cure. <h3>Objectives</h3> To test the hypothesis that CTLA4-Ig (abatacept), a biological DMARD that blocks co-stimulatory signals such as those provided by helper T cells to B cells, can impact on IDA, as evidenced by the induction of a silent, non-proliferative phenotype of ACPA-expressing mBC. <h3>Methods</h3> We conducted a single-center, randomized, open-label clinical trial in which patients with newly diagnosed, untreated RA (n=42) were treated with either methotrexate (MTX, n=21) or abatacept/MTX (ABA/MTX) combination therapy (n=21) for 6 months. Frequency and phenotypic characteristics of peripheral blood ACPA-expressing B cells were assessed directly ex-vivo by flow-cytometry at baseline (BL), 3 months (V2) and 6 months (V3). The expression of Ki-67 (primary endpoint), CD80, CD86 and HLA-DR were used to determine the activation state of the B cells in either group, next to B cell lineage and differentiation markers. Tetanus-toxoid (TT) specific B cells served as antigen-specific controls. Clinical disease characteristics as well as serum parameters were assessed in parallel. Differences between treatment groups were statistically analyzed using a mixed effect model with random slope and intercept. <h3>Results</h3> Of patients receiving treatment, n=14 in the ABA/MTX and n=16 in the MTX monotherapy arm harboured ACPA-expressing mBC in the circulation at sufficient frequency for phenotypic analysis. Patients with untreated RA exhibited a highly active ACPA mBC response, in line with previous results [1]. Both MTX and ABA/MTX reduced clinical disease activity at 6 months to a similar extent (p=0.33). The frequency of circulating ACPA-expressing mBC remained unaffected in either group. However, while ACPA-expressing mBC maintained their highly active phenotype in the MTX group, ABA/MTX impacted on the ACPA mBC response by significantly reducing the expression of Ki-67, CD86 and CD80. The expression of HLA-DR did not change upon treatment. <h3>Conclusion</h3> The ASCARA study provides first evidence that the activation of ACPA-expressing mBC can be therapeutically modulated towards a phenotype compatible with immunological remission. ABA/MTX, but not MTX alone had this modulatory effect, indicating that potentially important immunological drivers of RA disease processes are resistant to MTX-mediated effects. Interestingly, the phenotype induced by ABA/MTX resembles that observed in patients in sustained drug-free remission as well as in individuals with clinically suspect arthralgia that do not convert to RA (long-term non-converters, (1)). Follow-up analysis of the ASCARA study with ABA discontinuation beyond V3 will elucidate the stability of this effect and its relation to clinical disease characteristics. <h3>Reference</h3> [1] Kristyanto et al., Sci Transl Med. 2020 Nov 18;12(570):eaaz5327 <h3>Acknowledgements</h3> This study was financially supported by Bristol Myers Squibb within the EU/EFPIA Innovative Medicines Initiative Joint Undertaking (IMI2-JU) project RTCure. <h3>Disclosure of Interests</h3> Nienke Blomberg: None declared, Joanneke Kwekkeboom: None declared, Stefan Böhringer: None declared, Thomas Huizinga Speakers bureau: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb, Rene Toes Grant/research support from: Bristol Myers Squibb, Hans Ulrich Scherer Speakers bureau: Bristol Myers Squibb, Grant/research support from: Bristol Myers Squibb.